The main question addressed in this project is, "Do pathologic abnormalities of nerve microvessels play a role in the pathogenesis of diabetic neuropathies?" The studies address which vessels are involved, what are the pathologic processes, at what stage of development of neuropathy and by the influence of which risk factors? Cranial nerves III and VI, lumbosacral roots and systematically sampled levels of peripheral nerves at postmortem, and sural nerve at biopsy, from diabetics with and without neuropathy, and from healthy subjects, are to be studied by neuropathologic and morphom metric approaches to determine the three-dimensional pattern of fiber loss, regeneration and pathologic abnormality characteristic of different diabetic neuropathies. In endoneurial microvessels, the number of endothelial and pericyte muclei and the areas of lumen (LA), endothelial cells (EA), pericytes (PA), basement membrane (BMA), and wall (WA) are to be measured in electron micrographs. In epineurial arterioles, the number if endothelial, intimal and medial nuclei and LA, EA, medial area (MA), and WA are to be estimated in transverse semi-thin epoxy sections using our Imaging System for Nerve Morphometry (ISNM). The type and patterns of fiber pathologic abnormality are to be compared to patterns found in human neuropathies of known cause and especially to experimentally induced models of ischemic injury, neuronal degeneration and diffuse Schwann cell disease. Is the pattern of fiber loss and pathology like that of ischemic injury or of another mechanism? Is the severity of pathologic alterations of epineurial arterioles and endoneurial microvessels associated? Is the severity of pathologic alterations of microvessels associated with fiber pathology? Using serial semi-thin and thin sections the stereologic arrangement of terminal arteriole- capillary-venule (ACV) units are to be reconstructed in control and diabetic nerve looking for altered patterns of vascularization in diabetic neuropathy. Using the characteristics patterns of pathologic alterations found in experimental models of ischemic neuropathy, human diabetic nerves are to be critically studied looking for ischemic cores. If ischemic cores are found, are they found in early neuropathy or only in advanced neuropathy? Non- diabetic neuropathies are also to be studied assessing for specificity of vascular lesions in diabetic neuropathy. To search for insights as to cause of vessel and fiber alteration in diabetic neuropathy, pathologic alterations of vessels and fibers will be induced in rats by: a) ambient hypoxia, b) arterial ligation, c) microsphere embolization, d) single and mulitple nerve crush, e) lead neuropathy, and f) toxic and genetically induced diabetes.